|Year : 2022 | Volume
| Issue : 3 | Page : 246-253
Assessment of onset and progression of chemoradiotherapy induced oral complications in head and neck cancer patients - A prospective study
V Sharon Keziah, Sreedevi Dharman, Gopal Maragathavalli
Department of Oral Medicine and Radiology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
|Date of Submission||02-Jan-2022|
|Date of Decision||04-Sep-2022|
|Date of Acceptance||04-Sep-2022|
|Date of Web Publication||26-Sep-2022|
Department of Oral Medicine and Radiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Patients with head and neck cancer (HNC) undergoing chemoradiotherapy (CRT) are susceptible to acute oral complications that have deleterious effects on oral health, reducing the patients' quality of life. Aim: To assess the onset and progression of oral complications in head and neck cancer patients undergoing chemoradiotherapy. Materials and Method: This was a prospective study conducted among 40 patients with HNC undergoing CRT. Oral complications onset and grades of severity at different time points on a weekly basis for six weeks were assessed. Weekly pairwise comparisons of oral complications was done using the Friedman one-way repeated measure analysis of variance (ANOVA). The Chi-squared test was done in oral candidiasis to determine the significance between groups (P < 0.05). Results: Among 40 HNC patients who completed CRT and showed oral complications, 27 (67.5%) were males and 13 (32.5%) females, with peak age of 51–60 years (40%). All the oral complications had onset first noticed in the second week of CRT except dysphagia that occurred in the first week. A statistically significant difference in oral complications grading during week 1 to week 6 with P < 0.001 was present. All the patients had oral mucositis (OM), xerostomia, and dysgeusia observed in the fourth week, and dysphagia in fifth week. Severity in grading was noticed in the sixth week for all the complications. Candida albicans were more predominantly found in the later weeks as the dose of CRT increased (P < 0.001). Conclusion: In our study, a majority of oral complications had onset by second week of CRT and disease severity progressed in the sixth week of CRT. Awareness of the nature of oral complications by clinicians will aid in developing novel strategies and management in the near future that may help to improve the quality of life of the patient with HNC undergoing CRT.
Keywords: Candidiasis, chemoradiotherapy, dysphagia oral mucositis, xerostomia
|How to cite this article:|
Keziah V S, Dharman S, Maragathavalli G. Assessment of onset and progression of chemoradiotherapy induced oral complications in head and neck cancer patients - A prospective study. J Indian Acad Oral Med Radiol 2022;34:246-53
|How to cite this URL:|
Keziah V S, Dharman S, Maragathavalli G. Assessment of onset and progression of chemoradiotherapy induced oral complications in head and neck cancer patients - A prospective study. J Indian Acad Oral Med Radiol [serial online] 2022 [cited 2022 Dec 3];34:246-53. Available from: http://www.jiaomr.in/text.asp?2022/34/3/246/356960
| Introduction|| |
Head and neck cancer (HNC) refers to epithelial malignant tumors arising from the upper aerodigestive tract. HNC patients receiving chemoradiotherapy (CRT) are anticipated to affect radiosensitive tissue situated near the tumor, resulting in debilitating, life-threatening, adverse effects. Oral mucositis, sores with pain, dry mouth, taste changes, and oral infections are some of the common oral complications in these patients. Oral mucositis (OM) is the initial complication to arise in almost all patients undergoing CRT., In patients undergoing radiation therapy for a six to seven–week cycle, OM presents within the first two to three weeks as erythema of the oral mucosa which gradually progresses to ulceration as the dosage increases., Candidiasis is another common complication seen in HNC patients receiving CRT. In severe cases, there will be alteration in taste or dysgeusia, and loss of taste sensation due to radiation-sensitive taste buds.. Xerostomia is a major acute complication caused due to damage to the salivary gland by radiation leading to less or no salivary secretion. Swallowing problems are common and negatively impact the patient's quality of life. Other long-term oral complications include radiation caries, trismus, and osteoradionecrosis. The aim of this study was to assess the onset and progression of oral complications in HNC patients undergoing CRT.
| Materials and Method|| |
This was a prospective study done for a time period of six months from December 2021 to June 2022 where oral complications in patients with HNCs undergoing CRT were analyzed. The study was performed according to ethical guidelines of the Dr. Rai CBCC Center, Chennai, India. The current study was approved by the institution's ethical board of the institution –SDC- Institutional Human Ethical Committee (IHEC) and was in accordance with the Helinski declaration. The IHEC reference number is IHEC/SDC/UG-1769/21/325. Informed consent was acquired from all the patients.
The inclusion criteria were: (1) Patient's willingness to participate in the study; (2) Patients over 18 years of age willing to undergo CRT for HNC with no previous history of irradiation or chemotherapy given. All patients received radiotherapy to the HNC site five days per week (2 Gy/day) to 60 Gy for six weeks totally. Chemotherapy was based on weekly administration of cisplatin 40 mg/m2. The exclusion criteria were the disagreement of the patients to participate in the study.
In this prospective study, patients were selected using simple random sampling, and oral complications of 40 HNC patients during six weeks of CRT were evaluated. The 40 patients with sample size calculation using 95% confidence interval (CI) with an α value of 0.05 with expected reduction of 20% will provide a statistical power of more than 80%. Gender, age, clinical examination of oral mucositis, xerostomia, dysphagia, dysgeusia, and candidiasis were evaluated by a well-trained dentist weekly for six weeks after chemoradiotherapy sessions. The photographs of the oral complications were taken with informed consent of the patients. OM was classified according to the World Health Organization (WHO) classification on a 0–4 staging system.
Grade 0: No changes.
Grade 1: Erythema, soreness in the mucosa.
Grade 2: Erythema along with ulcers, soreness; patients can eat solid food.
Grade 3: Extensive erythema and ulcers with pain where the patient is limited to only a liquid diet.
Grade 4: Symptoms that are severe that necessitate enteral or parenteral feeding support for the patients.
Xerostomia was classified according to Seminars in Radiation Oncology.
Grade 0: No change.
Grade 1: Discrete symptoms and no dietary changes.
Grade 2: Symptoms with significant dietary changes (requiring liquid to swallow).
Grade 3: Severe symptoms, interference with diet, sleeping, speaking, tube-feeding.
Dysphagia and dysgeusia were assessed according to the National Cancer Institute Common Toxicity Criteria.
Dysphagia: Grade 0 indicating no change; grade 1, indicating minor swallowing difficulties, normal diet; grade 2 indicating moderate swallowing problems, liquid diet (cannot eat solid diet); grade 3 indicating severe swallowing problems, liquid diet, if possible tube-feeding; grade 4 indicating complete obstruction, no oral intake possible (cannot swallow saliva), ulceration and bleeding by trauma, tube-feeding.
Dysgeusia: Grade 0 indicating no changes; grade 1 indicating discrete palatal alteration; grade 2 indicating severe palatal alteration
Methods of isolation of Candida species
Candida was cultured by collecting whole saliva due to the debilitated state of the HNC patients receiving CRT with restricted mouth opening and xerostomia, where the affected area was difficult to access. It is more sensitive and is standardized with viable organisms can be isolated. Unstimulated whole saliva samples were collected by a spitting method for five minutes on a weekly basis for six weeks. The whole saliva was processed and streaked in a sterile culture media, following which they were incubated at 37°C for 24 hours. Yeast isolates were identified based on colony morphology in HiChrome Candida Differential Agar.
Prevalence of grading of oral complications at different time points on a weekly basis for six weeks were done by descriptive statistics. Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 24 (IBM; New York, USA). Weekly pairwise comparisons of oral complications was done using the Friedman one-way repeated measures analysis of variance (ANOVA). The Chi-squared test was done in oral candidiasis to determine the significance between groups wherein P < 0.05 was considered statistically significant.
| Results|| |
Forty-nine patients participated in this study to receive CRT for HNC. Nine patients were excluded as they could not continue with cancer treatment due to hospitalization. Forty patients completed CRT and underwent weekly evaluation for complications for six weeks. Twenty-seven males (67.5%) and 13 females (32.5%) participated in the present study, aged 18 years and above and with peak age being 51–60 years (40%) and 41–50 years (37.5%). Prevalence of grading of oral complications at different time-points on a weekly basis for six weeks is depicted in [Table 1]. Mean rank of weekly grading of oral complications by the Friedman one-way repeated measures ANOVA is depicted in [Table 2] and showed a statistically significant difference between weeks in all complications (P < 0.001). [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d shows grades 1, 2, 3, 4 OM in patients with HNC receiving CRT. [Figure 2]a and [Figure 2]b shows xerostomia and oral candidiasis in patients with HNC receiving CRT.
|Table 1: Descriptive statistics depicting prevalence of grading of oral complications at different time-points on weekly basis for six weeks|
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|Table 2: Assessment of mean rank of weekly gradings of oral complications (oral mucositis, xerostomia, dysphagia, dysgeusia) by the Friedman one-way repeated measures ANOVA|
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|Figure 1: (a-d) Grades 1, 2, 3, 4 oral mucositis in head and neck cancer patients receiving chemoradiotherapy|
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|Figure 2: (a and b) Xerostomia and oral candidiasis in head and neck cancer patients receiving chemoradiotherapy|
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Oral mucositis was first seen in week 2 with 20% having grade 1. Almost all of the patients had clinical manifestations of OM in the fourth week. Sixty percent had severe (graded 3 and 4) oral mucositis in the sixth week which showed the progression and severity of the disease. The highest percentage of grades 1, 2, and 3 mucositis was seen in the third, fifth, and sixth week of CRT with 62.5%, 62.5%, and 45%, respectively. Boxplot depicts the distribution of different grades of OM during the six weeks of CRT [Figure 3].
|Figure 3: Boxplot depicts the distribution of different grades of oral mucositis during the six weeks of CRT. Grade 2 oral mucositis was more prevalent in the fifth week of CRT. Grade 3 oral mucositis was more prevalent in the sixth week of CRT|
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The first sign of xerostomia categorized as grade 1 was seen in 14 patients (35%) in the second week of CRT. As the weeks of treatment progressed, the degree and severity of xerostomia was observed to be more. By the fifth week, all the participants exhibited some degree of xerostomia and in the sixth week of CRT, 15 (37.5%) patients were showing grade 3 xerostomia. Boxplot depicts the distribution of different grades of xerostomia during the six weeks of CRT [Figure 4].
|Figure 4: Boxplot depicts the distribution of different grades of xerostomia during the six weeks of CRT. Grade 1 xerostomia was more prevalent in the third week of CRT. Grade 2 xerostomia was more prevalent in the fifth week of CRT|
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Only 14 patients (35%) showed grade 1 dysphagia in the first week. There was a comparatively slower progression of the severity of dysphagia than xerostomia, with the transition from grade 1 to grade 2 dysphagia from the first week till the fourth week of CRT. In the fifth week of CRT, grade 3 dysphagia was observed in 15 patients (37.5%) and in the sixth week, 6 patients (15%) exhibited grade 4 dysphagia. Boxplot depicts the distribution of different grades of dysphagia during the six weeks of CRT [Figure 5].
|Figure 5: Boxplot depicts the distribution of different grades of dysphagia during the six weeks of CRT. Grade 1 dysphagia was seen more in the third week of CRT. All the patients exhibited dysphagia in the fifth week; grade 3 dysphagia was more prevalent in the fifth week of CRT|
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Dysgeusia was first seen in the second week of CRT where 45% of the cases were grade 1. By the fourth week of CRT, all of the patients exhibited some degree of dysgeusia. The highest percentage of grade 2 dysphagia was observed in the sixth week of dysphagia in 82.5% of cases. Boxplot depicts the distribution of different grades of dysgeusia during the six weeks of CRT [Figure 6].
|Figure 6: Boxplot depicts the distribution of different grades of dysgeusia during the six weeks of CRT. Grade 1 dysgeusia was more prevalent in the fourth week of CRT. Grade 2 dysgeusia was more prevalent in the sixth week of CRT|
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The fungal microbiota identified were Candida albicans and Candida tropicalis which were majorly found from week 2 of CRT in HNC patients. Steady increase in fungal colonization as week progressed in week 3 at 37.5% and at 37.5%, respectively, to week 6 at 85% were observed. Candida albicans (79.4%, n = 27/34) and Candida tropicalis (58.8%, n = 20/34) were found in the sixth week of CRT. Bar graph shows the prevalence of candidiasis during the six weeks of CRT [Figure 7]. Weekly pairwise comparisons of oral candidiasis was done using the Chi-squared test [Table 3]. [Figure 8] shows Candida albicans and Candida tropicalis colonies identified in HiChrome Candida Differential Agar.
|Figure 7: Bar graph shows the prevalence of candidiasis during the six weeks of CRT. The prevalence of candidiasis increased as the weeks of CRT progressed|
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|Figure 8: Hi-chrome Candida differential agar shows Candida albicans and Candida tropicalis in Head and Neck Cancer patients receiving chemoradiotherapy |
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|Table 3: Weekly pairwise comparison of oral candidiasis done by the Chi-squared test|
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| Discussion|| |
A total of 49 patients participated in receiving CRT for HNC. Nine patients were excluded as they could not continue with treatment due to hospitalization. Among the 40 HNC patients in our study, 27 were males and 13 were females, aged 51–60 years and undergoing CRT for HNC over a period of six weeks. In accordance with our study, a study done in Iran had 34 males and 20 females, with peak age being 60–69 years, undergoing CRT. The various oral complications that were observed in said study included oral mucositis, xerostomia, dysphagia, dysgeusia, candidiasis.
Oral mucositis is a painful complication which can significantly affect the nutritional intake and quality of life. In the present study, by the fourth week of CRT, all the HNC patients displayed some grade of OM with the severity worsening as the week of CRT progressed. The most severe cases (grade 3 and 4) of mucositis were seen in the sixth week of CRT with 45% and 15%, respectively. Studies, conducted among the HNC patients receiving CRT reported that the first sign of oral mucositis could be seen around the second week of radiotherapy, which was in line with the present study. Saedi et al., in their study conducted in the north of Iran, observed similar results, with a 16.7% prevalence rate of the most severe cases in the sixth week of radiotherapy. Prevention strategies for OM can be planned before the commencement of radiation treatment and might significantly reduce the occurrence of this complication.
Another common complication that was observed was xerostomia. It usually occurs due to damage in the salivary gland tissues when more than 50 Gy of radiation dose is received and/or because of certain chemotherapeutic drugs which affect the salivary flow rate. The first sign of grade 1 xerostomia was seen in the second week of CRT with a 35% prevalence rate. The highest number of severe types of xerostomia (grade 3) was observed in the sixth week of CRT where 15 out of 40 patients showed signs. The results of our study were consistent with a study done by Palmierie et al., where a majority of patients exhibited grade 3× erostomia in the sixth week of radiotherapy.
Most of the patients undergoing CRT develop some degree of dysphagia by the fifth week of radiotherapy. In the present study, the most severe cases (grade 4) of dysphagia were seen only during the last week of CRT (15%) wherein no oral intake by the patient was possible, they could not swallow saliva, and they needed tube-feeding. In a study by van der Laan et al., acute dysphagia was evident in 3–6 weeks of radiotherapy, which were prognostic factors for grades 2–4 dysphagia. Dysphagia negatively affects quality of life and leads to aspiration and life-threatening pulmonary complications.
Dysgeusia occurs due to damage to taste buds due to CRT. In our study, there was worsening from the third week to sixth week of CRT, with 10% being affected with grade 2 to 82% by the sixth week. Palmierie et al. first observed dysgeusia in the second week of radiotherapy, with severity observed in the third and fifth weeks.
In non-pathological conditions, the most common characteristic oral flora is the Candida oragnism. Under pathological circumstances there is a shift of Candida from commensalism to pathogen. Candida was the most prevalent fungal organism observed in this study. In our study, fungal isolation was done by salivary collection, as clinically diagnosed erythematous candidiasis, angular cheilitis are masked by radiation-induced OM and difficulty in accessing sites. A simple swab can be done but they are site-specific and are difficult to standardize. In concordance with our study, a systematic review by group from MASCC/ISOO revealed that fungal colonization during radiotherapy was 74.5%—slightly lower than our study. In a study done in Thailand where patients received radiotherapy for HNC, Candida albicans was the most commonly encountered species, with 82% being isolated from lesions; the second was C. tropicalis and C. glabrata. Similarly, in our study, C. albicans were 79.4% followed by the C. tropicalis with 58.8%. In our previous study, there was an increase in microbiota and shift in microbes as treatment progressed from day 1 to day 30 with more predominance of candida and Gram-negative species.
HNC patients undergoing chemoradiotherapy are prone to acute oral complications that affect their quality of life. It is very important to educate the patient about the importance of maintaining oral health to help reduce the symptoms of acute oral complications. Therefore, there is a need to develop better strategies and management to treat these symptoms, which may help to improve the quality of life of these patients.
Limitations: Limitations included small sample size following exclusion of patients due to hospitalization and the study being carried out for a shorter duration. A larger cohort study with longer post-treatment follow-ups are needed to study the exact nature of the disease.
Future prospects: Synthesizing newer drugs with efficient properties and fewer side effects is warranted and can prevent the onset and progression of oral complications in HNC patients receiving CRT.
| Conclusion|| |
In our study, OM was a major complication associated with HNC patients undergoing CRT. Mild-to-moderate (grades 1 and 2) OM was evident in the third and fourth week of CRT, and moderate-to-severe (grades 3 and 4) OM was seen in the 6th week of CRT. The majority of oral complications had onset by the second week of CRT, and disease severity was evident in the sixth week as CRT dose increased. Hence, dentists should be aware of such effects to hinder these complications and to educate patients to follow proper oral hygiene protocols and usage of novel drugs with effective properties and less side effects to improve patients' quality of life before, during, and after CRT.
Patients receiving CRT for HNC are prone to experiencing acute oral complications which are debilitating, thus hindering cancer therapy. Knowledge of onset and progression of these complications help patients to follow proper oral hygiene protocols before, during, and after CRT, dentist to instill novel strategies to prevent and treat, that improves patients quality of life.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3]